In February 1866 an IRB Council of War called for an immediate uprising, but Stephens refused, to Devoy's annoyance as he calculated the Fenian force in the British Army to number 80,000. The British got wind of the plan through informers and moved the regiments abroad, replacing them with regiments from Britain. Devoy was arrested in February 1866 and interned in Mountjoy Gaol then tried for treason and sentenced to fifteen years penal servitude. In Portland Prison, Devoy organised prison strikes and was moved to Millbank Prison in Pimlico, London.

In January 1871, he was released and exiled to America as one of the "Cuba Five". He received an address of welcome from the House of Representatives. Devoy became a journalist for the New York Herald and was active in Clan na Gael. Under Devoy's leadership, Clan na Gael became the central Irish republican organisation in the United States. In 1877 he aligned the organisation with the Irish Republican Brotherhood in Ireland.

Devoy's fundraising efforts and work to sway Irish-Americans to support physical force nationalism during World War I included attempts to assist the Easter Rising in 1916. In 1914, Padraig Pearse visited the elderly Devoy in America, and later the same year Roger Casement worked with Devoy in raising money for guns to arm the Irish Volunteers.

At the declaration of war between Britain and Germany on 14 August 1914, Sir Roger Casement and Devoy arranged a meeting in New York between the Western Hemisphere's top-ranking German diplomat, Count von Bernstorff, and a delegation of Clan-na-Gael men. The Clan delegates proposed a mutually beneficial plan: if Germany would sell guns to the Irish rebels and provide military leaders, the rebels would revolt against Britain, diverting troops and attention from the war with Germany. Von Bernstorff listened with evident sympathy and promised to relay the proposal to Berlin. Devoy decided to communicate directly with Berlin. At the time, Britain held control of the seas; within days of the start of the war it had cut the transatlantic cable. It would be necessary to send an envoy to deliver the message personally[8].

John Kenny, president of the New York Clan na Gael, was sent. After meeting the German ambassador in Rome and presenting Devoy's plan, Kenny met in Germany with Count von Bulow. He then travelled to Dublin where he told Tom Clarke and other members of the Irish Republican Brotherhood of the arrangement, and carried back to Devoy the IRB's wishlist for guns, money, and military leaders. The details of Kenny's mission were later published in the Gaelic American.

Though he was sceptical of the endeavour, Devoy financed and supported Casement's expedition to Germany to enlist German aid in the struggle to free Ireland from British rule, including Casement's Irish Brigade. Nervous of Casement's companion Adler Christensen, whom he discovered was a fraudster, and of Casement's decision to put the Irish Brigade at the Germans' disposal in Turkey, Devoy advised Casement to return to the USA, advice which was ignored.

In 1915 Joseph Plunkett visited Devoy in the US and Casement and diplomats Germany, meeting Devoy and setting up a deal with the Germans that Ireland would remain independent if Germany helped the coming Easter Rising by supplying guns and expertise and an attack on Britain simultaneous with the Rising. These guns were supplied, in the SS Aud; Devoy was blamed by the leaders of the Rising for failing to follow instructions that the guns should arrive on Easter Sunday, set for the start of the Rising; the IRB men sent to meet the Aud drove off a pier in the dark and were drowned, and the boat was scuttled by its captain and the guns sent to the bottom of the sea. Casement was captured as a result of the same mistiming.

In 1916 Devoy played an important role in the formation of the Clan-dominated Friends of Irish Freedom at the third Irish Race Convention, a propaganda organisation whose membership totalled at one point 275,000. The Friends supported Woodrow Wilson for the presidency in 1916 because of his policy of American neutrality in the world war. Fearful of accusations of disloyalty for their co-operation with Germans and opposition to the United States' entering the war on the side of Great Britain, the Friends lowered their profile after April 1917 when America entered the war.

With the end of the war, Devoy played a key role in the Friends' advocacy for self-determination for Ireland, in line with Wilson's "Fourteen Points", as distinct from recognition by the United States of the sovereignty of the newly declared Irish Republic. Wilson did not guarantee recognition of the Republic, as declared in 1916 and reaffirmed in the popular election in 1918. American-Irish republicans challenged the Friends' refusal to campaign for American recognition of the Irish Republic.Devoy and the Friends' Daniel F. Cohalan became the key players in a transatlantic dispute with de facto Irish president Éamon de Valera, who toured the United States in 1919 and 1920 in hopes of gaining US recognition of the Republic and American funds. Believing that the Americans should follow Irish policy, de Valera formed the American Association for the Recognition of the Irish Republic in 1920 with help from the Philadelphia Clan na Gael. Diplomatic recognition was not yet forthcoming, and Irish-American groups refused to support Wilson in the United States presidential election, 1920. $5.5m was raised to aid the new Irish nation.